Antibody responses to COVID‐19 vaccination in people with obesity: A systematic review and meta‐analysis

Abstract COVID‐19 vaccine is critical in preventing SARS‐CoV‐2 infection and transmission. However, obesity's effect on immune responses to COVID‐19 vaccines is still unknown. We performed a meta‐analysis of the literature and compared antibody responses with COVID‐19 vaccines among persons with and without obesity. We used Pubmed, Embase, Web of Science, and Cochrane Library to identify all related studies up to April 2022. The Stata.14 software was used to analyze the selected data. Eleven studies were included in the present meta‐analysis. Five of them provided absolute values of antibody titers in the obese group and non‐obese group. Overall, we found that the obese population was significantly associated with lower antibody titers (standardized mean difference [SMD] = −0.228, 95% CI [−0.437, −0.019], P < 0.001) after COVID‐19 vaccination. Significant heterogeneity was present in most pooled analyses but was reduced after subgroup analyses. No publication bias was observed in the present analysis. The Trim and Fill method did not change the results in the primary analysis. The present meta‐analysis suggested that obesity was significantly associated with decreased antibody responses to SARS‐CoV‐2 vaccines. Future studies should be performed to unravel the mechanism of response to the COVID‐19 vaccine in obese individuals.

Currently, different vaccines against SARS-CoV-2 have been implemented worldwide to reduce COVID-19 cases. However, obesity is associated with reduced memory immune responses. 8  (ChAdOx1), was one of the earliest authorized. 11,12 (3) Inactivated vaccines and subunit vaccines: The inactivated virus cannot replicate but can still produce immunogenicity. Subunit vaccines usually contain protein or peptide antigens derived from pathogens. 13 The efficacy of a vaccine is determined by the difference in the incidence of specific diseases among vaccinated and unvaccinated subjects for the disease. The immune responses to vaccines are evaluated by serological and/or immunological markers. The immune response could be conveniently partitioned into innate and adaptive immunity, in which the adaptive immunity is divided into 2 classes, including cell-mediated and humoral responses. 14 Humoral responses, only a part of immune responses, are easier to detect than other responses because of wide availability and standardization. The COVID-19 vaccine induces detectable humoral antibodies against different antigens of severe acute SARS-CoV-2. One of the major immunogenic antigens in the post-vaccine immune response is the transmembrane Spike (S), a receptor-binding domain (RBD) that protrudes from the surface of the spherical virions and mediates virus entry into host cells. 15 However, the antibody titers after vaccination remain significantly unpredictable, and many factors may influence it. Age, 16 gender, 17 and the number of doses 18 have been shown to influence antibody titers following COVID-19 vaccination.
Several systematic reviews of studies on COVID-19 vaccine efficacy and effectiveness have been published. [19][20][21][22] Nevertheless, none focused on the efficacy of COVID-19 vaccination in people with obesity. Therefore, the present study sought to investigate the associations between obesity and serum antibodies after COVID-19 vaccination.

| METHOD
This study was designed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. 23 The protocol of this systematic review was registered in PRISMA (CRD42022373514). Vaccine" and "obesity or overweight or body mass index." We have provided a detailed search strategy in Table S1.

| DATA EXTRACTION
For eligible studies, both review authors independently extracted the data. All disagreements were resolved by the third investigator (Junping Wen). The following data were extracted from each included study: first author, publication year, country, vaccine type, number of patients in each reported BMI range, days after vaccination, history of the previous infection with COVID-19, and outcomes. In this meta-analysis, quality assessment of included studies was conducted using the criteria of the Newcastle-Ottawa Scale (NOS). 24 The NOS scores ranged from 0 to 9. A study with NOS scores ≥6 was indicated to be of high quality.

| STATISTICAL ANALYSIS
A meta-analysis was performed by Stata14.0 software (Stata Corp, College Station, TX, USA). The primary outcomes of this analysis were the titers of post-vaccination antibodies presented as mean with standard deviation. The I 2 statistic was used to evaluate heterogeneity across the studies. When I 2 < 50%, the fixed effect model was used to combine data sets. Otherwise, the random effect model was applied. We planned to carry out the following subgroup analyses for the primary outcomes. Moreover, we conducted a subgroup metaanalysis when heterogeneity was ultra (I 2 > 50%).  Figure 1. To reduce error and explore the differences between the groups, we decided not to pool the data.   Two studies reported the baseline antibody titers. One of these contained six small groups. As shown in Figure 4, participants with obesity increase had a smaller increase of antibody titer compared with the non-obese group (SMD = À0.465, 95% CI [À0.612, À0.318], P = 0.001), yet heterogeneity was still present (I 2 = 73.5%).
Sensitivity analysis of the meta-analysis showed that they deviated symmetrically from the center axis ( Figure S2). The result indicated that patients infected with COVID-19 already had a certain antibody level. Not only that, antibody levels in individuals with obesity were higher. The above results show that immune response to the vaccine seems to be affected by the elapsed time since vaccination and history of previous SARS-CoV-2 infection.

| Risk of bias of included studies
In the meta-analysis of antibody positivity rates, the funnel plot was not strongly suggestive of publication bias ( Figure 6). Findings of Egger's test (P = 0.290, P = 0.138) suggested that publication bias was not significant. Furthermore, we applied the trim-and-fill method to this meta-analysis by using Metatrim. It has been presented in Figures S3 and S4, and the results showed that no trimming was performed, further suggesting no publication bias. Also, we adopted the trim-and-fill method to the meta-analysis of antibody titers, and six assumed studies with favorable effects were added, and the pooled Additionally, visual inspection of funnel plots revealed no obvious indication of publication bias, and statistical investigation of publication bias, using the Egger intercept, was nonsignificant. In the present study of antibody titers, applying the trim-and-fill method by using the Trim and Fill method indicated that our conclusions were reliable because the results remained unchanged after six assumed studies.
However, we observed a higher heterogeneity among 5 included This study shows that being overweight or obese is associated with lower antibody titers after COVID-19 mRNA vaccination.
Obesity is a metabolic problem and a chronic inflammatory disease. It increases the risk of metabolic disorders such as hyperglycemia, hyperlipidemia, hypercholesterolemia, and diabetes. 40 Accumulating excess fat causes chronic inflammation, damages the immune system, and thus impairs antibody formation. 41 In addition, obesity is associated with reduced immunogenicity after hepatitis B, 49 tetanus, 50  In conclusion, long-term COVID-19 vaccine efficacy in these patients should be closely monitored to limit further effects of COVID-19 on patients and society with obesity.

| CONCLUSIONS
In summary, the present meta-analysis suggested that obesity is significantly associated with the decreased antibody response to COVID-19 vaccines. Patients with obesity generated significantly reduced antibody titers after COVID-19 vaccines compared to people with normal weight. Future studies should be performed to unravel this relationship to prevent COVID-19 infection and transmission.
Our research results will lay the foundation for further meaningful research. Future studies will conduct in-depth research on the mechanism of response to the COVID-19 vaccine in obese individuals.

ACKNOWLEDGMENTS
The study was funded by the National Key Research and supervision; writing-review and editing.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13078.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author (JPW), upon reasonable request.